Monocular Painless Vision Loss in the Emergency Department: Multipurpose Utility of Point-of-Care Ultrasound.

BACKGROUND: Eye-related symptoms are a common presentation in the emergency department (ED). The cases range from simple viral conjunctivitis to trauma-related eye injuries. One pathological condition that could lead to vision loss is retinal artery occlusion (RAO). Evaluating a patient with an eye symptom requires thorough eye examination and advanced imaging in certain instances. Consultation with an ophthalmologist is also necessary for cases that require treatment recommendations and further testing. In the ED, point-of-care ultrasound (POCUS) is a commonly used diagnostic tool that can be used for ocular examination. CASE REPORT: We reported a case of a 60-year-old man who presented with painless partial right-eye vision loss. POCUS showed decreased flow in the right central retinal artery with an area of the pale retina seen on the image from the retinal camera, suggesting a possible branch RAO. Further examination with POCUS showed plaque formation at the carotid bifurcation, a potential cause of the patient's symptoms. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Emergency physicians and other providers should be encouraged to use POCUS to diagnose eye symptoms accurately and promptly. Abnormal findings will prompt immediate specialty consult and early appropriate management. Our case and other reported cases highlight POCUS's reliability and rapid diagnostic ability.

Maintaining the Utility of Coronavirus Disease 2019 Pandemic Severity Surveillance: Evaluation of Trends in Attributable Deaths and Development and Validation of a Measurement Tool.

BACKGROUND: Death within a specified time window following a positive SARS-CoV-2 test is used by some agencies for attributing death to COVID-19. With Omicron variants, widespread immunity, and asymptomatic screening, there is cause to re-evaluate COVID-19 death attribution methods and develop tools to improve case ascertainment. METHODS: All patients who died following microbiologically confirmed SARS-CoV-2 in the Veterans Health Administration (VA) and at Tufts Medical Center (TMC) were identified. Records of selected vaccinated VA patients with positive tests in 2022, and of all TMC patients with positive tests in 2021-2022, were manually reviewed to classify deaths as COVID-19-related (either directly caused by or contributed to), focused on deaths within 30 days. Logistic regression was used to develop and validate a surveillance model for identifying deaths in which COVID-19 was causal or contributory. RESULTS: Among vaccinated VA patients who died ≤30 days after a positive test in January-February 2022, death was COVID-19-related in 103/150 cases (69%) (55% causal, 14% contributory). In June-August 2022, death was COVID-19-related in 70/150 cases (47%) (22% causal, 25% contributory). Similar results were seen among the 71 patients who died at TMC. A model including hypoxemia, remdesivir, and anti-inflammatory drugs had positive and negative predictive values of 0.82-0.95 and 0.64-0.83, respectively. CONCLUSIONS: By mid-2022, "death within 30 days" did not provide an accurate estimate of COVID-19-related death in 2 US healthcare systems with routine admission screening. Hypoxemia and use of antiviral and anti-inflammatory drugs-variables feasible for reporting to public health agencies-would improve classification of death as COVID-19-related.

Progressive disseminated histoplasmosis: The experience in one non-endemic medical center.

Histoplasmosis, the most common endemic mycosis in North America, presents in a myriad of ways, spanning the spectrum from self-limiting pneumonia to progressive disseminated histoplasmosis (PDH). Toward better describing contemporary histoplasmosis syndromes, risks, and outcomes, this single-center retrospective cohort study was performed (2009-2019). The population who developed PDH was similar to that with other forms of histoplasmosis (OFH) except for higher rates of preexisting immunocompromising conditions (91.3% vs. 40%, P < .001) and a trend toward receiving more chronic immunosuppression (65.2% vs. 33.3%, P = .054) compared to those with OFH. Diagnosis was most frequently achieved by urinary or serum antigen positivity. People with PDH more frequently tested positive compared to those with OFH, but negative tests did not rule out histoplasmosis. Median time to diagnosis was prolonged among people with both PDH and OFH (32 vs. 31 days, respectively). Following diagnosis, people with PDH received more liposomal amphotericin (78.3% vs. 20%, P < .001). Subsequent survival at 90 and 365 days and treatment response were similar in both groups. Patients with PDH were more often hospitalized (95.7% vs. 60%, P = .006); however, once admitted, there were no differences in hospital length of stay or intensive care unit admission rate. The challenges of diagnosing histoplasmosis based on clinical presentation alone highlight the need for heightened awareness of these entities especially given the recent reports on expanded endemicity and delays in diagnosis.

Histoplasmosis is the most common endemic mycosis in North America. This article summarizes the clinical features, risk factors, and outcomes in patients who developed disseminated disease compared to more localized forms of histoplasmosis.

Active surveillance for PTMC warranted for the UK population?

BACKGROUND: The incidence of thyroid cancer is increasing globally due to the increase in detection of subclinical, low volume papillary thyroid microcarcinomas (PTMC) (<1 cm). Several international groups have recommended an active surveillance approach for this low-risk disease. In contrast to many other countries, the United Kingdom's (UK's) approach to thyroid nodules is to avoid detection of incidental lesions where appropriate. OBJECTIVE: This study aims to establish the proportion of patients with thyroid cancer in the UK that would benefit from active surveillance. DESIGN, PARTICIPANTS, AND OUTCOME MEASURES: Individuals with PTMC in NHS Lothian from 2009-2020 were reviewed from a local thyroid cancer database. The mode of detection of PTMC and proportion of patients who might benefit from active surveillance were established. RESULTS: From 651 individuals with differentiated thyroid cancer managed over 12-year period, 185 individuals with PTMC were identified (28.4%). The majority of PTMC 151/185 (81.6%) were either diagnosed post-operatively following thyroidectomy for benign disease or with nodal disease. Only 24 individuals with PTMC were identified following palpable thyroid nodule, incidental finding on imaging, and surveillance screening. Therefore, when the indication for surgery was considered, only 24/651 (3.7%) patients were identified pre-operatively and would, therefore, be realistic candidates for active surveillance. CONCLUSION: Less than 4% of patients with thyroid cancer in the UK would be appropriate for active surveillance. Rather than developing programmes to deal with this minority of patients, focus should be maintained on minimising detection of these low-risk cases.

Estimation of Secondary Household Attack Rates for Emergent Spike L452R Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Variants Detected by Genomic Surveillance at a Community-Based Testing Site in San Francisco.

BACKGROUND: Sequencing of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral genome from patient samples is an important epidemiological tool for monitoring and responding to the pandemic, including the emergence of new mutations in specific communities. METHODS: SARS-CoV-2 genomic sequences were generated from positive samples collected, along with epidemiological metadata, at a walk-up, rapid testing site in the Mission District of San Francisco, California during 22 November to 1 December, 2020, and 10-29 January 2021. Secondary household attack rates and mean sample viral load were estimated and compared across observed variants. RESULTS: A total of 12 124 tests were performed yielding 1099 positives. From these, 928 high-quality genomes were generated. Certain viral lineages bearing spike mutations, defined in part by L452R, S13I, and W152C, comprised 54.4% of the total sequences from January, compared to 15.7% in November. Household contacts exposed to the "California" or "West Coast" variants (B.1.427 and B.1.429) were at higher risk of infection compared to household contacts exposed to lineages lacking these variants (0.36 vs 0.29, risk ratio [RR] = 1.28; 95% confidence interval [CI]: 1.00-1.64). The reproductive number was estimated to be modestly higher than other lineages spreading in California during the second half of 2020. Viral loads were similar among persons infected with West Coast versus non-West Coast strains, as was the proportion of individuals with symptoms (60.9% vs 64.3%). CONCLUSIONS: The increase in prevalence, relative household attack rates, and reproductive number are consistent with a modest transmissibility increase of the West Coast variants. Summary: We observed a growing prevalence and modestly elevated attack rate for "West Coast" severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants in a community testing setting in San Francisco during January 2021, suggesting its modestly higher transmissibility.

Play, Learn, and Teach Outdoors-Network (PLaTO-Net): terminology, taxonomy, and ontology.

BACKGROUND: A recent dialogue in the field of play, learn, and teach outdoors (referred to as "PLaTO" hereafter) demonstrated the need for developing harmonized and consensus-based terminology, taxonomy, and ontology for PLaTO. This is important as the field evolves and diversifies in its approaches, contents, and contexts over time and in different countries, cultures, and settings. Within this paper, we report the systematic and iterative processes undertaken to achieve this objective, which has built on the creation of the global PLaTO-Network (PLaTO-Net). METHODS: This project comprised of four major methodological phases. First, a systematic scoping review was conducted to identify common terms and definitions used pertaining to PLaTO. Second, based on the results of the scoping review, a draft set of key terms, taxonomy, and ontology were developed, and shared with PLaTO members, who provided feedback via four rounds of consultation. Third, PLaTO terminology, taxonomy, and ontology were then finalized based on the feedback received from 50 international PLaTO member participants who responded to ≥ 3 rounds of the consultation survey and dialogue. Finally, efforts to share and disseminate project outcomes were made through different online platforms. RESULTS: This paper presents the final definitions and taxonomy of 31 PLaTO terms along with the PLaTO-Net ontology model. The model incorporates other relevant concepts in recognition that all the aspects of the model are interrelated and interconnected. The final terminology, taxonomy, and ontology are intended to be applicable to, and relevant for, all people encompassing various identities (e.g., age, gender, culture, ethnicity, ability). CONCLUSIONS: This project contributes to advancing PLaTO-based research and facilitating intersectoral and interdisciplinary collaboration, with the long-term goal of fostering and strengthening PLaTO's synergistic linkages with healthy living, environmental stewardship, climate action, and planetary health agendas. Notably, PLaTO terminology, taxonomy and ontology will continue to evolve, and PLaTO-Net is committed to advancing and periodically updating harmonized knowledge and understanding in the vast and interrelated areas of PLaTO.

Unstable chromosome rearrangements in Staphylococcus aureus cause phenotype switching associated with persistent infections.

Staphylococcus aureus small-colony variants (SCVs) are associated with unusually chronic and persistent infections despite active antibiotic treatment. The molecular basis for this clinically important phenomenon is poorly understood, hampered by the instability of the SCV phenotype. Here we investigated the genetic basis for an unstable S. aureus SCV that arose spontaneously while studying rifampicin resistance. This SCV showed no nucleotide differences across its genome compared with a normal-colony variant (NCV) revertant, yet the SCV presented the hallmarks of S. aureus linked to persistent infection: down-regulation of virulence genes and reduced hemolysis and neutrophil chemotaxis, while exhibiting increased survival in blood and ability to invade host cells. Further genome analysis revealed chromosome structural variation uniquely associated with the SCV. These variations included an asymmetric inversion across half of the S. aureus chromosome via recombination between type I restriction modification system (T1RMS) genes, and the activation of a conserved prophage harboring the immune evasion cluster (IEC). Phenotypic reversion to the wild-type-like NCV state correlated with reversal of the chromosomal inversion (CI) and with prophage stabilization. Further analysis of 29 complete S. aureus genomes showed strong signatures of recombination between hsdMS genes, suggesting that analogous CI has repeatedly occurred during S. aureus evolution. Using qPCR and long-read amplicon deep sequencing, we detected subpopulations with T1RMS rearrangements causing CIs and prophage activation across major S. aureus lineages. Here, we have discovered a previously unrecognized and widespread mechanism of reversible genomic instability in S. aureus associated with SCV generation and persistent infections.

Antibiotic stewardship in direct-to-consumer telemedicine: translating interventions into the virtual realm.

Direct-to-consumer (DTC) telemedicine is an increasingly popular modality for delivery of medical care via a virtual platform. As most DTC telemedicine visits focus on infection-related complaints, there is growing concern about the magnitude of antibiotic use associated with this setting. However, there is limited scholarship regarding adapting and implementing antibiotic stewardship principles in this setting as most efforts have been focused on hospitals with more recent work in long-term care facilities and primary care settings. We discuss utilizing the core elements for outpatient antibiotic stewardship as a framework for DTC antibiotic stewardship efforts moving forward.

Conventional T cell therapies pave the way for novel Treg therapeutics.

Approaches to harness the immune system to alleviate disease have become remarkably sophisticated since the crude, yet impressively-effective, attempts using live bacteria in the late 1800s. Recent evidence that engineered T cell therapy can deliver durable results in patients with cancer has spurred frenzied development in the field of T cell therapy. The myriad approaches include an innumerable variety of synthetic transgenes, multiplex gene-editing, and broader application to diseases beyond cancer. In this article, we review the preclinical studies and over a decade of clinical experience with engineered conventional T cells that have paved the way for translating engineered regulatory T cell therapies.

A minimal model for household-based testing and tracing in epidemics.

In a previous work (Huberet al.2020Phys. Biol.17065010), we discussed virus transmission dynamics modified by a uniform clustering of contacts in the population: close contacts within households and more distant contacts between households. In this paper, we discuss testing and tracing in such a stratified population. We propose a minimal tracing strategy consisting of random testing of the entire population plus full testing of the households of those persons found positive. We provide estimates of testing frequency for this strategy to work.

A small molecule interacts with VDAC2 to block mouse BAK-driven apoptosis.

Activating the intrinsic apoptosis pathway with small molecules is now a clinically validated approach to cancer therapy. In contrast, blocking apoptosis to prevent the death of healthy cells in disease settings has not been achieved. Caspases have been favored, but they act too late in apoptosis to provide long-term protection. The critical step in committing a cell to death is activation of BAK or BAX, pro-death BCL-2 proteins mediating mitochondrial damage. Apoptosis cannot proceed in their absence. Here we show that WEHI-9625, a novel tricyclic sulfone small molecule, binds to VDAC2 and promotes its ability to inhibit apoptosis driven by mouse BAK. In contrast to caspase inhibitors, WEHI-9625 blocks apoptosis before mitochondrial damage, preserving cellular function and long-term clonogenic potential. Our findings expand on the key role of VDAC2 in regulating apoptosis and demonstrate that blocking apoptosis at an early stage is both advantageous and pharmacologically tractable.

A Review of Corrosion in Aircraft Structures and Graphene-Based Sensors for Advanced Corrosion Monitoring.

Corrosion is an ever-present phenomena of material deterioration that affects all metal structures. Timely and accurate detection of corrosion is required for structural maintenance and effective management of structural components during their life cycle. The usage of aircraft materials has been primarily driven by the need for lighter, stronger, and more robust metal alloys, rather than mitigation of corrosion. As such, the overall cost of corrosion management and aircraft downtime remains high. To illustrate, $5.67 billion or 23.6% of total sustainment costs was spent on aircraft corrosion management, as well as 14.1% of total NAD for the US Air Force aviation and missiles in the fiscal year of 2018. The ability to detect and monitor corrosion will allow for a more efficient and cost-effective corrosion management strategy, and will therefore, minimize maintenance costs and downtime, and to avoid unexpected failure associated with corrosion. Conventional and commercial efforts in corrosion detection on aircrafts have focused on visual and other field detection approaches which are time- and usage-based rather than condition-based; they are also less effective in cases where the corroded area is inaccessible (e.g., fuel tank) or hidden (rivets). The ability to target and detect specific corrosion by-products associated with the metals/metal alloys (chloride ions, fluoride ions, iron oxides, aluminum chlorides etc.), corrosion environment (pH, wetness, temperature), along with conventional approaches for physical detection of corrosion can provide early corrosion detection as well as enhanced reliability of corrosion detection. The paper summarizes the state-of-art of corrosion sensing and measurement technologies for schedule-based inspection or continuous monitoring of physical, environmental and chemical presence associated with corrosion. The challenges are reviewed with regards to current gaps of corrosion detection and the complex task of corrosion management of an aircraft, with a focused overview of the corrosion factors and corrosion forms that are pertinent to the aviation industry. A comprehensive overview of thin film sensing techniques for corrosion detection and monitoring on aircrafts are being conducted. Particular attention is paid to innovative new materials, especially graphene-derived thin film sensors which rely on their ability to be configured as a conductor, semiconductor, or a functionally sensitive layer that responds to corrosion factors. Several thin film sensors have been detailed in this review as highly suited candidates for detecting corrosion through direct sensing of corrosion by-products in conjunction with the aforementioned physical and environmental corrosion parameters. The ability to print/pattern these thin film materials directly onto specific aircraft components, or deposit them onto rigid and flexible sensor surfaces and interfaces (fibre optics, microelectrode structures) makes them highly suited for corrosion monitoring applications.

Cryptococcus neoformans Evades Pulmonary Immunity by Modulating Xylose Precursor Transport.

Cryptococcus neoformans is a fungal pathogen that kills almost 200,000 people each year and is distinguished by abundant and unique surface glycan structures that are rich in xylose. A mutant strain of C. neoformans that cannot transport xylose precursors into the secretory compartment is severely attenuated in virulence in mice yet surprisingly is not cleared. We found that this strain failed to induce the nonprotective T helper cell type 2 (Th2) responses characteristic of wild-type infection, instead promoting sustained interleukin 12p40 (IL-12p40) induction and increased IL-17A (IL-17) production. It also stimulated dendritic cells to release high levels of proinflammatory cytokines, a behavior we linked to xylose expression. We further discovered that inducible bronchus-associated lymphoid tissue (iBALT) forms in response to infection with either wild-type cryptococci or the mutant strain with reduced surface xylose; although iBALT formation is slowed in the latter case, the tissue is better organized. Finally, our temporal studies suggest that lymphoid structures in the lung restrict the spread of mutant fungi for at least 18 weeks after infection, which is in contrast to ineffective control of the pathogen after infection with wild-type cells. These studies demonstrate the role of xylose in modulation of host response to a fungal pathogen and show that cryptococcal infection triggers iBALT formation.

Investigating Transfusion-related Sepsis Using Culture-Independent Metagenomic Sequencing.

BACKGROUND: Transfusion-related sepsis remains an important hospital infection control challenge. Investigation of septic transfusion events is often restricted by the limitations of bacterial culture in terms of time requirements and low yield in the setting of prior antibiotic administration. METHODS: In 3 gram-negative septic transfusion cases, we performed metagenomic next-generation sequencing (mNGS) of direct clinical blood specimens in addition to standard culture-based approaches utilized for infection control investigations. Pathogen detection leveraged IDSeq, a new open-access microbial bioinformatics portal. Phylogenetic analysis was performed to assess microbial genetic relatedness and understand transmission events. RESULTS: mNGS of direct clinical blood specimens afforded precision detection of pathogens responsible for each case of transfusion-related sepsis and enabled discovery of a novel Acinetobacter species in a platelet product that had become contaminated despite photochemical pathogen reduction. In each case, longitudinal assessment of pathogen burden elucidated the temporal sequence of events associated with each transfusion-transmitted infection. We found that informative data could be obtained from culture-independent mNGS of residual platelet products and leftover blood specimens that were either unsuitable or unavailable for culture or that failed to grow due to prior antibiotic administration. We additionally developed methods to enhance accuracy for detecting transfusion-associated pathogens that share taxonomic similarity to contaminants commonly found in mNGS library preparations. CONCLUSIONS: Culture-independent mNGS of blood products afforded rapid and precise assessment of pathogen identity, abundance, and genetic relatedness. Together, these challenging cases demonstrated the potential for metagenomics to advance existing methods for investigating transfusion-transmitted infections.

Xylose donor transport is critical for fungal virulence.

Cryptococcus neoformans, an AIDS-defining opportunistic pathogen, is the leading cause of fungal meningitis worldwide and is responsible for hundreds of thousands of deaths annually. Cryptococcal glycans are required for fungal survival in the host and for pathogenesis. Most glycans are made in the secretory pathway, although the activated precursors for their synthesis, nucleotide sugars, are made primarily in the cytosol. Nucleotide sugar transporters are membrane proteins that solve this topological problem, by exchanging nucleotide sugars for the corresponding nucleoside phosphates. The major virulence factor of C. neoformans is an anti-phagocytic polysaccharide capsule that is displayed on the cell surface; capsule polysaccharides are also shed from the cell and impede the host immune response. Xylose, a neutral monosaccharide that is absent from model yeast, is a significant capsule component. Here we show that Uxt1 and Uxt2 are both transporters specific for the xylose donor, UDP-xylose, although they exhibit distinct subcellular localization, expression patterns, and kinetic parameters. Both proteins also transport the galactofuranose donor, UDP-galactofuranose. We further show that Uxt1 and Uxt2 are required for xylose incorporation into capsule and protein; they are also necessary for C. neoformans to cause disease in mice, although surprisingly not for fungal viability in the context of infection. These findings provide a starting point for deciphering the substrate specificity of an important class of transporters, elucidate a synthetic pathway that may be productively targeted for therapy, and contribute to our understanding of fundamental glycobiology.

A minimal model for household effects in epidemics.

Shelter-in-place and other confinement strategies implemented in the current COVID-19 pandemic have created stratified patterns of contacts between people: close contacts within households and more distant contacts between the households. The epidemic transmission dynamics is significantly modified as a consequence. We introduce a minimal model that incorporates these household effects in the framework of mean-field theory and numerical simulations. We show that the reproduction number R 0 depends on the household size in a surprising way: linearly for relatively small households, and as a square root of size for larger households. We discuss the implications of the findings for the lockdown, test, tracing, and isolation policies.

Two cases of imported respiratory diphtheria in Edinburgh, Scotland, October 2019.

We report two cases of respiratory toxigenic Corynebacterium diphtheriae infection in fully vaccinated UK born adults following travel to Tunisia in October 2019. Both patients were successfully treated with antibiotics and neither received diphtheria antitoxin. Contact tracing was performed following a risk assessment but no additional cases were identified. This report highlights the importance of maintaining a high index of suspicion for re-emerging infections in patients with a history of travel to high-risk areas outside Europe.

The significance of vascular loops in the internal auditory meatus: a true incidental imaging finding?

PURPOSE: To determine the clinical significance of vascular loops (VL) in the internal auditory meatus (IAM) and cerebellopontine angle (CPA). METHODS: We carried out a retrospective case series in a tertiary referral centre. Out of 6978 patients undergoing magnetic resonance imaging (MRI) of the IAM for unilateral cochleovestibular symptoms we identified the ones with VLs and reviewed their medical notes. We performed a statistical correlation between the laterality of the VL in the IAM/ CPA as graded according to the Chavda classification (type 1 in the CPA, type 2 extending in the IAM, type 3 extending to the distal IAM end), the laterality of symptoms and the patient's age. RESULTS: A total of 77 VL were identified in 64 patients (0.9%); 39 patients had the VL on the same side of the main symptom, while 25 patients had the VL on the contralateral side. There were 37 Type 1 loops, 29 Type 2 loops and 11 Type 3 loops. The comparison between the grading of the VL and the laterality of symptoms did not reach the level of significance (p = 0.321). There was also no association between the presence of the loop and the patients' age (p = 0.5). All patients were reassured and discharged without any representation in three years follow-up. CONCLUSIONS: We did not identify any significant correlation between the laterality of VLs and the laterality of symptoms, irrespective of the grading of the loop or the patients' age. Such VLs should be considered an incidental rather than causal findings.

MEF2 transcription factors in human placenta and involvement in cytotrophoblast invasion and differentiation.

Development of the human placenta and its trophoblast cell types is critical for a successful pregnancy. Defects in trophoblast invasion and differentiation are associated with adverse pregnancy outcomes, including preeclampsia. The members of myocyte enhancer factor-2 (MEF2) family of transcription factors are key regulators of cellular proliferation, differentiation, and invasion in various cell types and tissues and might play a similarly important role in regulating trophoblast proliferation, invasion, and differentiation during human placental development. In the present study, using human cytotrophoblast cell lines (HTR8/SVneo and BeWo) and primary human cytotrophoblasts (CTBs), we show that members of the MEF2 family are differentially expressed in human placental CTBs, with MEF2B and MEF2D being highly expressed in first trimester extravillous CTBs. Overexpression of MEF2D results in cytotrophoblast proliferation and enhances the invasion and migration of extravillous-like HTR8/SVneo cells. This invasive property is blocked by overexpression of a dominant negative MEF2 (dnMEF2). In contrast, MEF2A is the principal MEF2 isoform expressed in term CTBs, MEF2C and MEF2D being expressed more weakly, and MEF2B expression being undetected. Overexpression of MEF2A induces cytotrophoblast differentiation and syncytium formation in BeWo cells. During in vitro differentiation of primary CTBs, MEF2A expression is associated with CTB differentiation into syncytiotrophoblast. Additionally, the course of p38 MAPK and ERK5 activities parallels the increase in MEF2A expression. These findings suggest individual members of MEF2 family distinctively regulate cytotrophoblast proliferation, invasion, and differentiation. Dysregulation of expression of MEF2 family or of their upstream signaling pathways may be associated with placenta-related pregnancy disorders.

Unraveling synthesis of the cryptococcal cell wall and capsule.

Fungal pathogens cause devastating infections in millions of individuals each year, representing a huge but underappreciated burden on human health. One of these, the opportunistic fungus Cryptococcus neoformans, kills hundreds of thousands of patients annually, disproportionately affecting people in resource-limited areas. This yeast is distinguished from other pathogenic fungi by a polysaccharide capsule that is displayed on the cell surface. The capsule consists of two complex polysaccharide polymers: a mannan substituted with xylose and glucuronic acid, and a galactan with galactomannan side chains that bear variable amounts of glucuronic acid and xylose. The cell wall, with which the capsule is associated, is a matrix of alpha and beta glucans, chitin, chitosan, and mannoproteins. In this review, we focus on synthesis of the wall and capsule, both of which are critical for the ability of this microbe to cause disease and are distinct from structures found in either model yeasts or the mammals afflicted by this infection. Significant research effort over the last few decades has been applied to defining the synthetic machinery of these two structures, including nucleotide sugar metabolism and transport, glycosyltransferase activities, polysaccharide export, and assembly and association of structural elements. Discoveries in this area have elucidated fundamental biology and may lead to novel targets for antifungal therapy. In this review, we summarize the progress made in this challenging and fascinating area, and outline future research questions.